Acyclovir (9((2-hydroxyethoxy)methyl)guanine) is an antiviral which inhibits human herpes viruses, including herpes simplex types 1 (HSV-1) and 2 (HSV-2), varicella zoster, Epstein-Barr virus (EBV) and cytomegalovirus (CMV). The inhibitory activity of acyclovir is highly selective for these viruses. O'Brien and Campoli-Richards, Drugs, 37:233-309 (1989). The chemical composition of acyclovir is reported in Shaffer, et al. (J. Med. Chem. 14:367 (1971)), U.S. Pat. No. 4,199,574, and UK Patent Specification No. 1,523,865, all of which are hereby incorporated by reference.
Acyclovir has been demonstrated to be a potent antiviral agent, particularly against herpes viruses. Shaffer, et al. Nature 272:583-585 (1978). Acyclovir has also been demonstrated to effectively suppress reactivated or newly acquired viral diseases such as genital herpes simplex, shingles, and varicella-zoster, as well as acute varicella-zoster infections. Balfour, J. Med. Virology, S1:74-81 (1993). Morbidity and mortality from viral disease have been reduced by pre- and postoperative prophylaxis with long-term (>6 months) oral acyclovir therapy. Prentice et al., Lancet 343:749-753 (1994). Concurrent acyclovir and AZT (azidothymidine) therapy has extended the survival of AIDS patients by one year when acyclovir therapy was begun at time of diagnosis. Stein, et al., Ann. Intern. Med. 121:100-108 (1994). Additionally, acyclovir therapy for acute varicella-zoster disease reduces fever, chronic pain, and the progression of rash and accelerates cutaneous healing.
Other uses include, but are not limited, to, mucocutaneous, ocular, and systemic herpes simplex infections (HSV), including in human immunodeficiency virus (HIV)-infected individuals. It is also useful to treat HSV encephalitis, neonatal HSV infections, and genital herpes (first episode, recurrent and suppressive therapy for recurrent infections). Further, acyclovir is effective therapy for varicella-zoster infections, herpes zoster (shingles, zoster), cytomegalovirus infections, infections and disorders associated with Epstein-Barr virus, and the Center for Disease Control states that oral acyclovir may be used in pregnant women. These and other uses are found in AHFS Drug Information, American Society of Health System Pharmacists, Bethesda, Md., 2005, which is incorporated by reference herein.
Acyclovir, is currently marketed as capsules, tablets and suspension for oral administration. Orally administered acyclovir is slowly and erratically absorbed with 15-30% bioavailability. Barnhart (ed.), Physicians' Desk Reference, Oradell, N.J.: Medical Economics Data (1994). Over half the dose of the currently marketed formulation is recovered in the feces. Schaeffer at al., Nature, 272:583-585 (1978). Failure to respond to acyclovir therapy may arise from an inadequate dose (frequency of dose or total daily dose); patient noncompliance; malabsorption in the intestine; or, resistant viral strains. Mindel, J. Med. Virology, S1:39-44 (1993). The need for readily absorbed oral antiviral agents has been identified as imperative for treatment of viral diseases to both patient populations since long term IV treatment is restrictive and compliance with currently available oral acyclovir formulations is difficult. Katlama, J. Med. Virology S1:128-133 (1993). An acyclovir preparation for oral delivery which permitted lower dosing and less frequent administration would facilitate compliance.
Previous attempts have been made to improve the oral delivery of acyclovir. U.S. Pat. No. 5,629,016, which is hereby incorporated, by reference, discloses water dispersible tablets containing acyclovir which facilitates the ingestion of large doses (i.e. up to 800 mg) of acyclovir. The tablets, however, do not improve the bioavailability of the acyclovir.
U.S. Pat. No. 5,883,103 discloses a microemulsion system for the oral delivery of acyclovir. The system includes a water-in-oil emulsion with acyclovir dispersed in aqueous phase droplets. The droplets have an average droplet size of 20-40 nanometers and are uniformly dispersed in the continuous oil phase.
Although, previous attempts have been made to improve the delivery and bioavailability of acyclovir, these attempts have had limited success. Therefore, there is a need for oral acyclovir formulations having increased bioavailability.